Spontaneous HIT syndrome

Case presentation

A 76-year-old woman underwent bilateral total knee arthroplasty without any complications.
Postoperative deep venous thrombosis (DVT) prophylaxis consisted of aspirin 81 mg
twice a day. Approximately two weeks after the procedure, the patient was transferred
from a rehabilitation center to the ED due to worsening dyspnea, chest pain, and oxygen
desaturation to 80% on room air.

Her medical history consisted of breast cancer treated with a lumpectomy. She did
not have personal or family history of venous thromboembolism. The patient did not
smoke tobacco and rarely drank alcohol. Outpatient medications included letrozole,
2.5 mg/d, and aspirin, 81 mg/d. An extensive review of the patient's perioperative
medication history did not reveal any exposure to heparin.

Upon presentation, the patient was afebrile with a blood pressure of 120/55 mm Hg,
a heart rate of 93 beats/min, a respiratory rate of 18 breaths/min, and oxygen saturation
of 93% on room air. Physical exam revealed a frail-appearing woman in mild distress.
Lung exam demonstrated decreased breath sounds bilaterally. Lower extremities had
mild pitting edema bilaterally. The remainder of the physical exam was within normal
limits.

An ultrasound of the lower extremities demonstrated an occlusive thrombus within the
right posterior tibial veins and occlusive thrombi within the left popliteal, gastrocnemius,
and posterior tibial veins. A CT angiogram of the chest revealed bilateral pulmonary
emboli without evidence of right ventricular strain. A transthoracic echocardiogram
confirmed no evidence of right ventricular strain.

The patient was started on subcutaneous enoxaparin, 80 mg every 12 hours and aspirin,
324 mg in the ED. The platelet level did not decrease with administration of enoxaparin.

Enoxaparin was discontinued on post-operative day 17 once HIT test results returned
positive. Subsequently, the patient was started on apixaban, 10 mg twice daily, for
seven days, followed by apixaban, 5 mg twice daily by mouth, for six months. Her platelet
count recovered after enoxaparin was withdrawn.

Background

HIT is a potentially life-threatening immune-mediated response caused by antibodies
recognizing specific complexes located on PF4 bound to heparin or heparin-related
compounds.

Diagnosis

Current diagnostic criteria for HIT utilize a pretest clinical score known as the
4T's score to differentiate patients with HIT from those with non-HIT thrombocytopenia
(1313. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced
thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-65. [PMID: 16634744]). The 4T's scoring system includes thrombocytopenia, timing of platelet count fall,
thrombosis or other sequelae, and other more likely causes for thrombocytopenia. According
to the points allocated for each item, patients are assigned to low-risk (0 to 3 points),
intermediate-risk (4 or 5 points), or high-risk groups (6 to 8 points). The probability
of HIT is estimated to be 0.2% (95% CI, 0.0% to 3.0%) in low-risk 4T's scorings, 14%
(95% CI, 9% to 22%) in intermediate-risk scorings and 64% (95% CI, 40% to 82%) in
high-risk scorings (1313. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced
thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-65. [PMID: 16634744]). It has been recommended that when assessing patients for possible spontaneous HIT
syndrome after knee replacement surgery (i.e., when there is no exposure to heparin),
knee surgery itself should be considered “time 0” for evaluating of
“timing” of platelet count fall (1414. Warkentin TE. 4Ts score for the diagnosis of HIT. ECAT. 2014;4 (Special Issue, Heparin-Induced Thrombocytopenia):18-22.). Using this approach, our patient would have scored 6 points (high probability for
HIT) based on: 2 points (Thrombocytopenia) + 1 point (Timing) + 2 points (Thrombosis)
+ 1 point (“oTher” explanation for thrombocytopenia, that is, thrombosis-associated
consumptive thrombocytopenia).

To corroborate a suspected diagnosis of HIT, it is crucial to perform laboratory testing
for HIT antibodies, preferably using both a PF4-dependent immunoassay (e.g., enzyme-immunoassay)
as well as a functional (platelet activation) assay, such as the serotonin release
assay (1717. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. [PMID: 22160026]). We performed both types of assay in our patient, and both yielded strong-positive
results. Given the strong clinical picture for spontaneous HIT syndrome, these test
results corroborate the diagnosis.

Classic HIT typically features a heparin-dependent immune response, where if there
is no heparin present in the sample, there is no serum-induced serotonin release.
These sera typically cause strong serotonin-release at low (pharmacologic) heparin
concentrations (0.1 to 0.5 IU/mL); at suprapharmacologic heparin concentrations (100
IU/mL), the amount of serotonin release is inhibited, usually by at least 50%. Inhibition
of serotonin release at 100 IU/mL heparin is a feature of both classic HIT and spontaneous
HIT syndrome and was seen with our patient (96% and 100% serotonin release at 0.1
and 0.15 U/mL of heparin, but only 31% serotonin release at 100 IU/mL of heparin).
In so-called autoimmune HIT syndromes, such as spontaneous HIT syndrome, heparin-independent
platelet activation can be seen, that is, strong serum-induced serotonin release even
in the absence of heparin. Unfortunately, U.S. laboratories typically do not perform
the serotonin release assay at 0 IU/mL of heparin, potentially contributing to under-recognition
of spontaneous HIT syndrome (1515. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia:
a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946], 1616. Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost. 2017;15:2099-2114. [PMID: 28846826]).

Treatment

Treatment for spontaneous HIT is very similar to that for an acute HIT episode. It
has been suggested that patients be treated with a non-heparin anticoagulant such
as argatroban, lepirudin, or bivalirudin (1717. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. [PMID: 22160026]). Fondaparinux is not as readily recommended because spontaneous HIT cases have been
reported with it and because exacerbation of thrombocytopenia and disseminated intravascular
coagulation (DIC) can occur with fondaparinux (22. Burch M, Cooper B. Fondaparinux-associated heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent).
2012;25:13-5. [PMID: 22275775], 1515. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia:
a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946]). The FDA-approved anticoagulant for treating HIT, argatroban, is not necessarily
effective in treating spontaneous HIT syndrome. In a recent review, seven spontaneous
HIT cases were treated with argatroban; treatment failed in five of those patients,
with one developing fatal hemorrhage and four having new-onset or progressive thrombosis
(1818. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls.
Expert Opin Drug Saf. 2014;13:25-43. [PMID: 23971903]). The authors suggested that this could be due to partial thromboplastin time (PTT)
“confounding.”

Understanding the baseline or pretreatment levels of PTT and international normalized
ratio (INR) can be instrumental in managing a patient with spontaneous HIT. PTT confounding
and INR confounding have resulted in misleading PTT and INR values. For example, a
patient with severe spontaneous HIT-associated DIC had high supratherapeutic levels
of PTT while being treated with argatroban (1818. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls.
Expert Opin Drug Saf. 2014;13:25-43. [PMID: 23971903]). The PTT levels were elevated due to the effects argatroban and DIC, leading the
physician to inappropriately reduce the amount of anticoagulation. The recommended
treatment would be rivaroxaban or fondaparinux. Indeed, our patient's “baseline”
PTT at time of presentation of spontaneous HIT syndrome was elevated (PTT, 39 s),
supporting the use of a DOAC rather than a PTT-adjusted therapy, with its attendant
risks of systematic underdosing due to PTT confounding. Therefore, argatroban may
not be suitable for treatment of spontaneous HIT.

Conclusion

Approximately 20 cases of spontaneous HIT have been reported previously (2121. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation
from non-HIT thrombocytopenia. Thromb Haemost. 2016;116:813-822. [PMID: 27656712]). This case demonstrates how both infection and total knee arthroplasty may be potential
causes of spontaneous HIT. After extensive review of her operative reports, it was
verified that this patient did not have any prior heparin exposure. Another key point
in diagnosing her with spontaneous HIT is that her platelet counts were very low even
before being exposed to heparin for the first time on postoperative day 13. Because
this is such a rare occurrence, more data need to be collected on patients presenting
with persistent thrombocytopenia and thrombotic events after orthopedic surgeries.

In summary, a patient presenting with a hypercoagulable state in the postoperative
setting without heparin exposure may be manifesting an autoimmune response now understood
to be spontaneous HIT syndrome. It is crucial to order baseline INR/PTT, serotonin
release assay (requesting that the laboratory perform the test also in the absence
of heparin as well as at pharmacologic and suprapharmacologic heparin concentrations),
and the PF4-heparin enzyme immunoassay to accurately diagnose this rare condition.
Recommended treatments are mainly direct oral anticoagulants such as rivaroxaban,
apixaban, or edoxaban or the direct thrombin inhibitor dabigatran. If a patient has
severe, refractory autoimmune HIT, high-dose intravenous immunoglobulin is an alternative
treatment option.

Ms. McCarthy is a medical student at the Philadelphia College of Osteopathic Medicine
in Philadelphia. Dr. Isaac is chief resident of internal medicine at Lankenau Medical
Center in Wynnewood, Pa. Dr. Cohen is an internist at Lankenau Medical Center with
a special interest in vascular disorders and is a clinical professor of medicine at
the Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia.

ACP Hospitalist provides news and information for hospitalists, covering the major issues in the field. All published material, which is covered by copyright, represents the views of the contributor and does not reflect the opinion of the American College of Physicians or any other institution unless clearly stated.